U.S. patent number 5,955,475 [Application Number 08/885,068] was granted by the patent office on 1999-09-21 for process for manufacturing paroxetine solid dispersions.
This patent grant is currently assigned to Endo Pharmaceuticals Inc.. Invention is credited to Sou-Chan Chang, William A. Hein, II, Philip J. Krape, Christopher A. Teleha.
United States Patent |
5,955,475 |
Krape , et al. |
September 21, 1999 |
Process for manufacturing paroxetine solid dispersions
Abstract
Solid dispersions of poorly soluble drugs are disclosed which
are prepared using a solvent or fusion process. Such dispersions
are manufactured with the free base of the drug, specifically
paroxetine free base, an oil, allowing for a low temperature for
the fusion process, decreased organic solvent volumes for the
solvent process and the formation of a paroxetine salt during the
solid dispersion manufacture process.
Inventors: |
Krape; Philip J. (Wilmington,
DE), Chang; Sou-Chan (Westbury, NY), Hein, II; William
A. (Hasbrouck Heights, NJ), Teleha; Christopher A.
(Bear, DE) |
Assignee: |
Endo Pharmaceuticals Inc.
(Chadds Ford, PA)
|
Family
ID: |
25386061 |
Appl.
No.: |
08/885,068 |
Filed: |
June 30, 1997 |
Current U.S.
Class: |
514/321;
514/937 |
Current CPC
Class: |
A61K
9/146 (20130101); A61K 9/2077 (20130101); A61P
25/24 (20180101); A61K 31/4525 (20130101); C07D
405/12 (20130101); Y10S 514/937 (20130101) |
Current International
Class: |
A61K
31/4525 (20060101); A61K 31/4523 (20060101); A61K
9/20 (20060101); C07D 405/00 (20060101); A61K
9/14 (20060101); C07D 405/12 (20060101); A61K
031/445 () |
Field of
Search: |
;514/321 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
4007146 |
February 1977 |
Christuensen et al. |
4721723 |
January 1988 |
Barnes et al. |
4933360 |
June 1990 |
Pandit et al. |
|
Foreign Patent Documents
|
|
|
|
|
|
|
WO 9515155 A1 |
|
Jun 1995 |
|
WO |
|
WO 9516448 A1 |
|
Jun 1995 |
|
WO |
|
WO 9631197 A1 |
|
Oct 1996 |
|
WO |
|
Primary Examiner: Schenkman; Leonard
Attorney, Agent or Firm: Schnader Harrison Segal & Lewis
LLP Fein; Michael B.
Claims
What is claimed is:
1. A process for preparing a water soluble solid state dispersion
of paroxetine salt and a pharmaceutically acceptable polymeric
carrier, which process comprises:
(a) forming a solution of a water soluble pharmaceutically
acceptable polymeric carrier and a non-aqueous solvent,
(b) dissolving paroxetine free base into the solution, wherein the
ratio by weight of water soluble pharmaceutically acceptable
polymeric carrier to paroxetine is in the range of about 4:1 to
about 1:1;
(c) contacting the paroxetine free base in solution with at least
one equivalent of an acid, wherein the acid is a non-toxic
inorganic or organic acid, to form a pharmaceutically acceptable
non-crystalline paroxetine salt anhydrate in solution; and
(d) removing non-aqueous solvent by evaporation under vacuum.
2. The process of claim 1 wherein said polymeric carrier is
selected from one or more of the following: polyvinylpyrrolidone,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl
cellulose, block co-polymers of ethylene oxide and propylene oxide,
and polyethylene glycol.
3. The process of claim 1 wherein paroxetine free base is dissolved
into a non-aqueous solvent before the polymeric carrier is
dissolved into the non-aqueous solvent.
4. The process of claim 1 wherein the non-aqueous solvent is an
alcohol selected from methanol, ethanol, n-propanol, iso-propanol,
n-butanol, iso-butanol, and sec-butanol.
5. The process of claim 1 wherein the non-aqueous solvent is
ethanol.
6. The process of claim 1 wherein the acid is hydrogen chloride in
the form of dry hydrogen chloride gas or dry hydrogen chloride
dissolved into a non-aqueous solvent.
7. The process of claim 1
wherein said polymeric carrier is polyvinylpyrrolidone.
8. The process of claim 7 wherein the polymeric carrier is
polyvinylpyrrolidone having an average molecular weight of from
about 2,500 to about 3,000,000.
9. The process of claim 7 wherein the non-aqueous solvent is an
alcohol selected from methanol, ethanol, n-propanol, iso-propanol,
n-butanol, iso-butanol, and sec-butanol.
10. The process of claim 7 wherein the non-aqueous solvent is
ethanol.
11. The process of claim 7 wherein the acid is hydrogen chloride in
the form of dry hydrogen chloride gas or dry hydrogen chloride
dissolved into a non-aqueous solvent.
12. The process of claim 7
wherein said solvent is ethanol, said acid is dry hydrogen
chloride, and wherein the dry hydrogen chloride is dissolved in
methanol or ethanol, to form pharmaceutically acceptable paroxetine
hydrogen chloride in solution.
13. A solid state dispersion of a pharmaceutically acceptable
polymeric carrier and noncrystalline paroxetine hydrochloride
anhydrate produced by the process of claim 12.
14. The process of claim 1
wherein said polymeric carrier is polyethylene glycol and said acid
is a non-toxic inorganic or organic acid.
15. The process of claim 14 wherein the polymeric carrier is
polyethylene glycol having an average molecular weight of from
about 1,000 to about 20,000.
16. The process of claim 14 wherein the non-aqueous solvent is an
alcohol selected from methanol, ethanol, n-propanol, iso-propanol,
n-butanol, iso-butanol, and sec-butanol.
17. The process of claim 14 wherein the non-aqueous solvent is
ethanol.
18. The process of claim 14 wherein the acid is hydrogen chloride
in the form of dry hydrogen chloride gas or dry hydrogen chloride
dissolved into a non-aqueous solvent.
19. The process of claim 14 wherein said solvent comprises
ethanol, said acid is dry hydrogen chloride, wherein the dry
hydrogen chloride is dissolved in methanol or ethanol and said
removing non-aqueous solvents comprises removing ethanol and, if
present, methanol.
20. A solid state dispersion of a pharmaceutically acceptable
polymeric carrier and noncrystalline paroxetine hydrochloride
anhydrate produced by the process of claim 1.
21. A process for preparing a water soluble solid state dispersion
of paroxetine and a pharmaceutically acceptable polymeric carrier,
which process comprises:
(a) contacting a water soluble pharmaceutically acceptable
polymeric carrier with paroxetine free base to form an intimate
mixture, wherein the ratio by weight of water soluble
pharmaceutically acceptable polymeric carrier to paroxetine free
base is in the range of about 4:1 to about 1:1;
(b) heating the mixture to form a molten homogeneous melt of
polymeric carrier and paroxetine free base;
(c) contacting the molten homogeneous melt of polymeric carrier and
paroxetine free base with at least one equivalent of dry hydrogen
chloride to form pharmaceutically acceptable noncrystalline
paroxetine hydrogen chloride anhydrate in the molten homogeneous
melt; and
(d) cooling the molten homogeneous melt to form a water soluble
solid state dispersion.
22. A process for preparing a water soluble solid state dispersion
of paroxetine and a pharmaceutically acceptable polymeric carrier,
which process comprises:
(a) contacting a polyethylene glycol with paroxetine free base to
form an intimate mixture, wherein the ratio by weight of
polyethylene glycol to paroxetine free base is in the range of
about 4:1 to about 1:1;
(b) heating the mixture to form a molten homogeneous melt of
polyethylene glycol and paroxetine free base;
(c) contacting the molten homogeneous melt of polyethylene glycol
and paroxetine free base with at least one equivalent of dry
hydrogen chloride to form pharmaceutically acceptable
noncrystalline paroxetine hydrogen chloride anhydrate in the molten
homogeneous melt; and
(d) cooling the molten homogeneous melt to form a water soluble
solid state dispersion.
23. A solid state dispersion comprising a pharmaceutically
acceptable polymeric carrier and noncrystalline paroxetine salt
anhydrate.
24. A pharmaceutical composition comprising a solid state
dispersion of claim 23 and one or mote pharmaceutically acceptable
excipients.
25. A pharmaceutical composition comprising a solid state
dispersion of claim 20 and one or more pharmaceutically acceptable
excipients.
26. A method of treating depression in a warm-blooded animal
comprising administering to said animal a solid state dispersion as
defined in claim 23, the amount of paroxetine hydrochloride in said
dispersion being effective for treating depression.
27. A method of treating depression in a warm-blooded animal
comprising administering to said animal a solid state dispersion as
defined in claim 20, the amount of paroxetine hydrochloride in said
dispersion being effective for treating depression.
Description
FIELD OF THE INVENTION
The present invention relates to the field of solid dispersions of
poorly water soluble drugs, to processes for their preparation and
their use in pharmaceutical compositions. Specifically, the present
invention relates to solid dispersions resulting from fusion or
solvent methods for the incorporation of poorly water soluble drugs
into pharmaceutically acceptable carriers. More specifically, the
invention relates to the solid dispersions of paroxetine, processes
for the preparation of such solid dispersions, pharmaceutical
compositions containing the same and their use thereof in
therapy.
BACKGROUND
The compound
(-)-trans-4-((4'-fluorophenyl)3-(3'4'-methylenedioxyphenoxymethyl)-piperid
ine, commonly known as paroxetine, is a viscous oil and poorly
water soluble drug with a commercial need for useful pharmaceutical
compositions. A solid dispersion of paroxetine or its acid addition
salt, never described before now in the literature, would provide a
solid product on a commercial scale with good handling qualities
and physiological acceptability without the need or expense to
manufacture crystalline materials.
Pharmaceutical compositions with good dissolution and
bioavailability can be formulated from solid dispersions of
pharmaceutically active ingredients. Advantages claimed for
pharmaceutical solid dispersions include potential use in
controlled release formulations, stabilizing the drug from
polymorphic conversions, improving poor handling properties of drug
substances and protecting certain drugs against decomposition
during administration. Solid dispersions of pharmaceutically active
ingredients can be formed from a number of pharmaceutically
acceptable carriers. U.S. Pat. No. 4,933,360 describes a novel
process and product comprising chlorthalidone as the pharmaceutical
active ingredient and polyvinylpyrrolidone (PVP) as the
pharmaceutically acceptable carrier. The techniques have been
described in general by W. L. Chiou et al., J. Pharm. Sci.
60(28)(1971) and S. Riegelman et al, U.S. Pat. No. 4,151,273. As
defined in the Chiou article the term "solid state dispersion"
means a dispersion of one or more active ingredients in an inert
carrier or matrix in a solid state prepared by a melting (fusion),
solvent, or combined melt-solvent method. The dispersion of an
active ingredient in a solid carrier or diluent by traditional
mechanical mixing is not included within the definition of this
term.
In the "solvent method", the active ingredient is conventionally
dispersed in a water soluble carrier by dissolving a physical
mixture containing the active ingredient and the pharmaceutically
acceptable carrier in a common organic solvent and then removing
the solvent by evaporation. The resulting solid dispersion is
recovered and used in the preparation of suitable pharmaceutical
compositions formulated using conventional methods.
Manufacture of solid dispersions by the fusion or "melt" process
involves combination of the pharmaceutically acceptable carrier and
the poorly water soluble drug where the two components are allowed
to melt at temperatures at or above the melting point of both the
drug and the carrier. In the fusion process, the drug and carrier
are first physically mixed and then both are melted. The molten
mixture is then cooled rapidly to provide a congealed mass which is
subsequently milled to produce a powder. Spray-congealing
techniques used to produce pellets have been described by Kanig (J.
Pharm. Sci. 53, 188 (1964)) for dispersions containing mannitol and
by Kreuschner et al. (Acta Pharm. Tech. 26, 159 (1980)) for
phenylbutazone-urea.
In general, problems which can be associated with known melting
(fusion), solvent, melt solvent, and coprecipitation techniques can
include excess solvent usage, identifying carrier/drug combinations
that can be conveniently melted (fused) or codissolved, the use of
heat to effect solution or fusion which may result in decomposition
of the drug and/or carrier, and identifying conditions and
properties effecting coprecipitation. Salts of drugs may present
particular problems with identifying organic solvents or solvents
capable of dissolving both the drug and a pharmaceutically
acceptable carrier.
U.S. Pat. No. 4,007,196 discloses paroxetine as an inhibitor of
5-hydroxytryptamine (5HT) uptake and thus of therapeutic use as an
anti-depressant. Paroxetine is well known and widely marketed as a
medicinal agent. As disclosed in U.S. Pat. No. 4,007,196,
paroxetine is obtained as the free base and then converted to its
maleate salt. However, paroxetine is a poorly water soluble drug
and difficult to formulate into useful pharmaceutical
compositions.
U.S. Pat. No. 4,721,723 indicates that because of its basicity, it
is preferred that paroxetine be used as a therapeutic agent in the
form of an acid addition salt. The free base is a viscous oil which
is difficult to handle and formulate into a finished dosage form
for therapeutic use. As such, U.S. Pat. No. 4,721,723 further
discloses crystalline paroxetine hydrochloride hemihydrate as a
novel material with better handling properties than anhydrous
paroxetine hydrochloride which is an hygroscopic solid with poor
handling properties.
In general, the hydrochloride salt of a basic compound is preferred
for therapeutic use because of its physiological acceptability.
Additionally, a pharmaceutically active ingredient should not
contain appreciable amounts of bound or unbound organic solvent.
Once the salt has been formed, it must be isolated from solvents by
filtration or other means in order for the paroxetine salt to be
conveniently formulated into a pharmaceutical composition. Many
solvents, including water, form solvates or clathrates of
paroxetine hydrochloride wherein the solvent cannot be removed by
conventional drying techniques such as vacuum oven drying. U.S.
Pat. No. 4,721,723 discloses the hemihydrate solvate form of
paroxetine hydrochloride while International Publication Number WO
96/24595 discloses paroxetine hydrochloride solvates other than the
propan-2-ol solvate as precursors in the preparation of paroxetine
hydrochloride substantially free of bound organic solvent.
Additionally, International Publication Number WO 96/24595 also
discloses four novel paroxetine hydrochloride anhydrates
substantially free of bound solvent. However, none of the above
publications specifically describe the stability or hygroscopicity
of noncrystalline anhydrates of paroxetine hydrochloride in a solid
dispersion.
The present invention relates to novel processes for incorporating
paroxetine, a poorly water soluble drug, into a solid dispersion
and its use in pharmaceutical compositions containing the same.
It has now been surprisingly found that solid dispersions of
anhydrous paroxetine hydrochloride can be manufactured by a fusion
process using the free base of paroxetine, and dry hydrogen
chloride gas at temperatures substantially lower then the melting
point of paroxetine hydrochloride using a pharmaceutically
acceptable carrier with a melting point significantly lower than
that of anhydrous paroxetine hydrochloride. The resulting solid
dispersion is substantially free of organic solvent, is anhydrous
and has improved handling properties.
Furthermore, it has been found that solid dispersions of anhydrous
paroxetine salts, preferably the hydrochloric acid salt, can be
manufactured by a novel solvent process using a pharmaceutically
acceptable carrier, paroxetine free base, a non-aqueous solvent and
a solution or gas of the acid addition salt.
The manufacturing of noncrystalline anhydrates of paroxetine
hydrochloride in a solid dispersion improves the formulating of
paroxetine free base, provides a solid which is readily formulated
into a commercial dosage form, eliminates the additional steps to
manufacture crystalline material for handling purposes and
presumptively reduces manufacturing costs associated with those
steps.
SUMMARY OF THE INVENTION
Solid dispersions of poorly soluble drugs are disclosed which are
prepared using a solvent or fusion process. Such dispersions are
manufactured with the free base of the drug, specifically
paroxetine free base, an oil, allowing for a low temperature for
the fusion process, decreased organic solvent volumes for the
solvent process and the formation of a paroxetine salt during the
solid dispersion manufacture process.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment the invention provides a process for
preparing a water soluble solid state dispersion of paroxetine and
a pharmaceutically acceptable polymeric carrier, which process
comprises:
(a) forming a solution of a water soluble pharmaceutically
acceptable polymeric carrier and a non-aqueous solvent,
(b) dissolving paroxetine free base into the solution, wherein the
ratio by weight of water soluble pharmaceutically acceptable
polymeric carrier to paroxetine is in the range of about 4:1 to
about 1:1;
(c) contacting the paroxetine free base in solution with at least
one equivalent of an acid, wherein the acid is a non-toxic
inorganic or organic acid, to form a pharmaceutically acceptable
paroxetine salt in solution; and
(d) removing the non-aqueous solvent by evaporation under
vacuum.
In a preferred embodiment the invention provides a process for
preparing a water soluble solid state dispersion wherein the
polymeric carrier is polyethylene glycol or
polyvinylpyrrolidone.
In a more preferred embodiment the invention provides a process for
preparing a water soluble solid state dispersion of paroxetine and
a pharmaceutically acceptable polymeric carrier, which process
comprises:
(a) forming a solution of polyethylene glycol and ethanol,
(b) dissolving paroxetine free base into the solution, wherein the
ratio by weight of polyethylene glycol to paroxetine is in the
range of about 4:1 to about 1:1;
(c) contacting the paroxetine free base in solution with at least
one equivalent of dry hydrogen chloride, wherein the dry hydrogen
chloride is dissolved in methanol or ethanol, to form
pharmaceutically acceptable paroxetine hydrogen chloride in
solution; and
(d) removing the non-aqueous solvent by evaporation under
vacuum.
In an even more preferred embodiment the invention provides a
process for preparing a water soluble solid state dispersion of
paroxetine and a pharmaceutically acceptable polymeric carrier,
which process comprises:
(a) forming a solution of polyvinylpyrrolidone and ethanol,
(b) dissolving paroxetine free base into the solution, wherein the
ratio by weight of polyvinylpyrrolidone to paroxetine is in the
range of about 4:1 to about 1:1;
(c) contacting the paroxetine free base in solution with at least
one equivalent of dry hydrogen chloride, wherein the dry hydrogen
chloride is dissolved in methanol or ethanol, to form
pharmaceutically acceptable paroxetine hydrogen chloride in
solution; and
(d) removing the non-aqueous solvent by evaporation under
vacuum.
In a second embodiment the invention provides a process for
preparing a water soluble solid state dispersion of paroxetine and
a pharmaceutically acceptable polymeric carrier, which process
comprises:
(a) contacting a water soluble pharmaceutically acceptable
polymeric carrier with paroxetine free base to form an intimate
mixture, wherein the ratio by weight of water soluble
pharmaceutically acceptable polymeric carrier to paroxetine free
base is in the range of about 4:1 to about 1:1 ;
(b) heating the mixture to form a molten homogeneous melt of
polymeric carrier and paroxetine free base;
(c) contacting the molten homogeneous melt of polymeric carrier and
paroxetine free base with at least one equivalent of dry hydrogen
chloride to form pharmaceutically acceptable paroxetine hydrogen
chloride in the molten homogeneous melt; and
(d) cooling the molten homogeneous melt to form a water soluble
solid state dispersion.
In a preferred second embodiment the invention provides a process
for preparing a water soluble solid state dispersion of paroxetine
and a pharmaceutically acceptable polymeric carrier, which process
comprises:
(a) contacting a polyethylene glycol with paroxetine free base to
form an intimate mixture, wherein the ratio by weight of
polyethylene glycol to paroxetine free base is in the range of
about 4:1 to about 1:1;
(b) heating the mixture to form a molten homogeneous melt of
polyethylene glycol and paroxetine free base;
(c) contacting the molten homogeneous melt of polyethylene glycol
and paroxetine free base with at least one equivalent of dry
hydrogen chloride to form pharmaceutically acceptable paroxetine
hydrogen chloride in the molten homogeneous melt; and
(d) cooling the molten homogeneous melt to form a water soluble
solid state dispersion.
In a third embodiment the invention provides a solid state
dispersion comprising a pharmaceutically acceptable polymeric
carrier and paroxetine.
In a fourth embodiment the invention provides for a pharmaceutical
composition comprising one or more pharmaceutically acceptable
excipients and a solid state dispersion comprising paroxetine and a
pharmaceutically acceptable polymeric carrier.
In a fifth embodiment the invention provides for a method of
treating depression in a warm-blooded animal comprising
administering to said animal a solid state dispersion, comprising
paroxetine and a pharmaceutically acceptable polymeric carrier, the
amount of paroxetine hydrochloride in said dispersion being
effective for treating depression.
By "paroxetine" it is meant the generic name for the compound
described in Example 2 of U.S. Pat. No. 4,007,196, also known as
(-)-trans-4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-piperi
dine, and pharmaceutically acceptable salts thereof. Therefore, as
used herein, the term paroxetine refers to "paroxetine free base"
or "paroxetine salt". The term "paroxetine free base", or simply
"free base", specifically refers to paroxetine as a material which
is a viscous oil at standard temperature and pressure. The term
"paroxetine salt" is used to describe an acid addition product of
paroxetine. For example, in the case of the hydrogen chloride, the
acid addition product is called "paroxetine hydrochloride" or
simply "hydrochloride salt."
The compound paroxetine herein described has two asymmetric
centers. Unless otherwise indicated, the (-)-trans isomer is the
preferred enantiomer. However, all chiral, diastereomeric and
racemic forms are included in the present invention. It is well
known in the art how to prepare optically active forms, such as by
resolution of racemic forms or by synthesis, from optically active
starting materials. Use of all chiral, diastereomeric, racemic
forms are intended, unless the specific stereochemistry or isomer
form is specifically indicated.
As used herein, the term "non-aqueous solvent" refers to any of the
following: methanol, ethanol, n-propanol, i-propanol, n-butanol,
i-butanol, s-butanol, toluene, benzene, supercritical liquid
CO.sub.2, chloroform, methylene chloride, acetonitrile, ketones
(for example, but not limited to, dimethylketone,
methylethylketone, and diethylketone), dimethylformamide,
dimethylsulfoxide, esters (for example, but not limited to, ethyl
acetate), ethers (for example, but not limited to, diethylether and
dipropylether), 1,4-dioxane, tetrahydrofuran, pentanes, hexanes,
heptanes, trichloroethene, or suitable mixtures of thereof.
Preferably the solvent should be (a) capable of dissolving both the
active ingredient and the carrier, (b) chemically inert with
respect to the active ingredient and the carrier, and (c)
sufficiently volatile to permit removal by evaporation using
conventional techniques. Alkanols having from one to four carbon
atoms would in general be expected to be useful for preparing solid
state dispersions by the solvent method. In the present invention
additional characteristics have been found to be important. The
organic solvent should be (d) capable of dissolving both the free
base and the pharmaceutically acceptable salt of the active
ingredient; (e) chemically inert with respect to both the free base
of the active ingredient and the salt formed after reaction with
the acidified organic solvent; and (f) capable of dissolving
sufficient acid to permit complete or nearly complete conversion of
the free base to the salt.
As used herein, the term "pharmaceutically acceptable polymeric
carrier", or "polymeric carrier" refers to any of the following:
hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose,
sodium carboxymethyl cellulose, cellulose acetate phthalate,
cellulose acetate butyrate, hydroxyethyl cellulose, ethyl
cellulose, polyvinyl alcohol, polypropylene, dextrans, dextrins,
hydroxypropyl-beta-cyclodextrin, chitosan, co(lactic/glycolid)
copolymers, poly(orthoester), poly(anhydrate), polyvinyl chloride,
polyvinyl acetate, ethylene vinyl acetate, lectins, carbopols,
silicon elastomers, polyacrylic polymers, maltodextrins, lactose,
fructose, inositol, trehalose, maltose, raffinose,
polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and alpha-,
beta-, and gamma-cyclodextrins, or suitable mixtures of
thereof.
In the present invention, additional characteristics have been
found to be important. The pharmaceutically acceptable carrier
should be (a) capable of being miscible with both the free base and
the salt form of the drug substance, (b) capable of keeping the
salt in a homogeneous noncrystalline solid state dispersion after
the solvent has been removed by evaporation and (c) chemically
inert with respect to the free base of the active ingredient, the
salt of the free base, and the acidified organic solvent.
As used herein, the term "pharmaceutically acceptable salt" refers
to derivatives of paroxetine wherein paroxetine is modified by
making acid addition salts of the compound. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of the basic piperidine residue; and
the like. The pharmaceutically acceptable salts of paroxetine
include conventional non-toxic salts or quaternary ammonium salts,
for example, from non-toxic inorganic or organic acids. For
example, such conventional non-toxic salts include those derived
from inorganic acids such as hydrochloric, hydrobromic, sulfuric,
sulfamic, phosphoric, nitric and the like; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic,
isethionic, and the like.
The pharmaceutically acceptable salts of paroxetine can be prepared
according to the method of the present invention would include
introduction of or delivery of the acid moiety by various means. In
the fusion method, the acidic moiety would be introduced in neat
form. In the solution method, the acidic moiety could be introduced
in neat form or by the non-aqueous solvent, which is later removed.
Generally, the salts are prepared by reacting the free base with
stoichiometric amounts or with an excess of the desired
salt-forming inorganic or organic acid.
Lists of suitable salts are found in Remington's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.
1418, the disclosure of which is hereby incorporated by
reference.
As used herein, the term "dry hydrogen chloride gas" refers to
hydrogen chloride gas commercially available in cylinders
containing compressed gas which is dried before use. Generally, dry
hydrogen chloride gas is commercially prepared by bubbling hydrogen
chloride gas through concentrated sulfuric acid or a comparable
drying agent.
The disclosure of all references used herein are hereby
incorporated by reference.
It is the object of the present invention to provide improved
processes for the preparation of a water soluble solid dispersion
of a poorly water soluble drug or drug combination prepared by a
fusion and/or solvent process for producing solid dispersions. The
methods of the present invention, by way of example, and without
limitation, may be further understood by the following descriptive
procedures.
The general method for preparation of a solid dispersion by the
solvent process proceeds by (1) forming a solution comprising a
pharmaceutically acceptable carrier and a non-aqueous solvent. A
preferred polymeric carrier is selected from one or more of
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, methyl cellulose, block co-polymers of ethylene oxide
and propylene oxide, and polyethylene glycol, wherein a more
preferred polymeric carrier is either polyethylene glycol (PEG)
having an average molecular weight of from about 1,000 to about
20,000 or polyvinylpyrrolidone (PVP) having an average molecular
weight of from about 2,500 to about 3,000,000. A most preferred
polymeric carrier is polyvinylpyrrolidone having an average
molecular weight of from about 10,000 to about 450,000. A preferred
non-aqueous solvent is an alcohol selected from methanol, ethanol,
n-propanol, iso-propanol, n-butanol, iso-butanol, and sec-butanol,
wherein a more preferred solvent is either methanol or ethanol,
wherein a most preferred solvent is ethanol. It is also preferred
that the non-aqueous solvent be dry or anhydrous. In forming a
solution of a polymeric carrier and a non-aqueous solvent it is
understood that heating of the solution is allowable, but is not
required, provided that the temperature does not result in
decomposition or degradation of any materials.
Upon forming said solution the process proceeds by (2) dissolving
the free base of a poorly water soluble drug in the solution thus
formed. Heating is allowable as in step (1) but not required. It is
understood that the addition of a poorly soluble drug is not
limited to one drug but might encompass a combination of one or
more drugs provided at least one drug is a poorly water soluble
drug in the form of a free base. It is preferred that the poorly
water soluble drug in the form of a free base is paroxetine. The
ratio by weight of water soluble pharmaceutically acceptable
polymeric carrier to paroxetine is in the range of about 5:1 to
about 1:1; preferably about 4:1 to about 1:1; more preferably about
3:1 to about 1.5:1; most preferably about 2:1.
It is also understood that the order of addition for the polymeric
carrier, the nonaqueous solvent and the free base of the poorly
water soluble drug is interchangeable. For example, the free base
drug could be dissolved into the non-aqueous solvent after which
the polymeric carrier is added.
Upon dissolution of the free base drug the process proceeds by (3)
converting the free base to a pharmaceutically acceptable
preferably the free base salt, preferably the paroxetine salt, can
be formed by addition of an inorganic or an organic acid which
preferably is non-toxic and pharmaceutically acceptable. The acid
is added either as a gas, a liquid or as a solid dissolved into a
nonaqueous solvent. The preferred acid is dry hydrogen chloride and
the molar quantity of acid added to the solution of paroxetine free
base and carrier may either be in stoichiometric proportion to the
paroxetine free base or be in excess of the molar quantity of the
paroxetine free base, especially when added as a gas. For example,
the preferred range of hydrogen chloride added is, but not limited
to, from about 1.0 to about 1.8 times the molar quantity of
paroxetine free base. Although dry hydrogen chloride is readily
added as a gas the preferred method to add the hydrogen chloride is
in the form of hydrogen chloride dissolved into a non-aqueous
solvent, preferably hydrogen chloride saturated methanol or
ethanol. It is understood that upon addition of the acid, the
formed free base salt remains dissolved in solution with the
polymeric carrier.
Lastly, upon formation of the free base salt, the process proceeds
by (4) recovering the non-aqueous solvent to form a solid state
dispersion of the free base salt in the polymeric carrier. Any
method of removal of the non-aqueous solvent which renders a
homogeneous solid state dispersion is intended, although preferred
are methods of evaporation under vacuum. Preferred methods of
evaporation under vacuum include rotoevaporation, static vacuum
drying and the combination thereof. It is understood that one
skilled in the art of pharmaceutical formulations can determine a
reasonable temperature at which the non-aqueous solvent can be
removed, provided the temperature is not so high as to cause
degradation or decomposition of the materials; however, it is
preferred that evaporation occurs at about 20.degree. C. to about
50.degree. C. It is also preferred that evaporation of the
non-aqueous solvent renders a solid state dispersion which is
homogeneous and substantially free of non-aqueous solvent. By
substantially free it is meant that the solid state dispersion
contains less than 20% by weight of residual non-aqueous solvent,
preferably less than 10%, more preferably less then 5%, most
preferably less then 1%.
The ratio of paroxetine free base to the pharmaceutically
acceptable carrier can be varied over a wide range and depends on
the concentration of paroxetine required in the pharmaceutical
dosage form ultimately administered. However, the preferred range
of paroxetine in the solid dispersion is about 16% to about 50% of
the total solid dispersion weight, more preferable is about 20% to
about 50%, even more preferable is about 25% to about 40%, most
preferable is about 33% of the total dispersion weight.
Alternatively, the general method for preparation of a solid
dispersion can proceed by a fusion process wherein a water soluble
pharmaceutically acceptable polymeric carrier is mixed with a
poorly water soluble drug, preferably paroxetine free base, or drug
combination, to form an intimate mixture. The mixture is heated at
or near the temperature of the highest melting point of either the
pharmaceutically acceptable carrier or poorly water soluble drug or
drug combination, thus forming a melt. A preferred polymeric
carrier is polyethylene glycol. A preferred ratio by weight of
water soluble pharmaceutically acceptable polymeric carrier to
poorly water soluble drug is in the range of about 5:1 to about
1:1; preferably about 4:1 to about 1:1; more preferably about 3:1
to about 1.5:1; most preferably about 2:1.
It is understood that the addition of a poorly soluble drug is not
limited to one drug but might encompass a combination of one or
more drugs provided at least one drug is a poorly water soluble
drug in the form of a free base. It is preferred that the poorly
water soluble drug in the form of a free base is paroxetine.
Alternatively, the water soluble pharmaceutically acceptable
polymeric carrier can be heated to molten condition upon which the
poorly water soluble drug, as the free base, can be added to the
molten carrier, thus forming a molten homogeneous melt.
Upon forming said molten homogeneous melt the process proceeds by
(2) diffusing dry hydrogen chloride gas through the molten
drug/carrier mixture to effect salt formation of the drug.
Lastly, upon formation of the free base salt, the process proceeds
by (4) cooling the molten homogeneous melt by conventional methods
to form a water soluble solid state dispersion.
The ratio of paroxetine free base to the pharmaceutically
acceptable carrier can be varied over a wide range and depends on
the concentration of paroxetine required in the pharmaceutical
dosage form ultimately administered. However, the preferred range
of paroxetine in the solid dispersion is about 16% to about 50% of
the total solid dispersion weight, more preferable is about 20% to
about 50%, even more preferable is about 25% to about 40%, most
preferable is about 33% of the total dispersion weight.
Alternatively, the general method for preparation of a solid
dispersion can proceed by a combination of the fusion method and
the solvent method.
Specifically, the poorly water soluble drug is paroxetine; for the
fusion process the preferred pharmaceutically acceptable carrier is
polyethylene glycol; for the solvent process the preferred
pharmaceutically acceptable carrier is polyvinylpyrrolidone or
polyethylene glycol, the preferred solvent is ethanol, the
preferred pharmaceutically acceptable salt is hydrogen chloride,
the preferred method to add the hydrogen chloride is in the form of
ethanolic hydrogen chloride and the preferred method to recover the
solvent is by evaporation at about 20.degree. C. to about
50.degree. C. by a combination of evaporation and static vacuum
drying.
The present invention also provides a pharmaceutical composition
comprising pharmaceutically acceptable excipients and a solid state
dispersion of paroxetine hydrochloride and pharmaceutically
acceptable polymeric carrier. Examples of pharmaceutically
acceptable excipients include diluents, binders, disintegrants,
coloring agents, flavoring agents, lubricants and/or preservatives.
The pharmaceutical composition may be formulated by conventional
methods of admixture such as blending, filling, granulation and
compressing. These agents may be utilized in conventional manner,
for example in a manner similar to that already used clinically for
anti-depressant agents.
The composition is usually presented as a unit dose composition
containing from 1 to 200 mg, more usually from 5 to 100 mg, for
example 10 to 50 mg such as 12.5, 20, 25, or 30 mg. Such
composition is normally taken from 1 to 6 times daily, for example
2,3, or 4 times daily so that the total amount of active agent
administered is within the range of 5 to 400 mg.
Preferred unit dosage forms include tablets or capsules.
The invention also provides for a method of treatment of depression
in mammals including humans which method comprises administering an
effective amount of pharmaceutically acceptable solid state
dispersion of paroxetine hydrochloride.
The invention further provides a solid state dispersion of
paroxetine hydrochloride for use in the treatment of
depression.
The following examples illustrate the invention. Examples 1-16,
show the preparation of solid state dispersions while Examples 17
and 18 show pharmaceutical compositions.
EXAMPLE 1
PEG-8000/Paroxetine Free-Base, 2:1 wt Basis; Fusion Method
To a 50 mL pear-shaped round bottom flask (equipped with a small
magnetic stir bar, rubber septa and a glass pipette) was added
PEG-8000 (2.009 g) and paroxetine free-base (0.75 g). The flask was
immersed into a water bath, which was heated to a temperature to
effect melting of the PEG. Once free-flowing, the glass pipette was
carefully lowered below the level of the melt, and a stream of
hydrogen chloride gas (dried through conc. sulfuric acid) was
bubbled through the pipette for 30 minutes. Stirring was maintained
during this process. After the gas introduction, the pipette and
the stir bar were removed and the mixture was allowed to cool to
room temperature overnight. The solidified product was carefully
scraped from the flask. This material could be optionally
ground/milled to a desirable particle size.
.sup.1 H NMR analysis (CDCl.sub.3) were wholly consistent with a
mixture of PEG and paroxetine hydrochloride, and shows the expected
resonance for PEG (3.63, m) and the characteristic signal for
paroxetine hydrochloride (2.03, br. d)
Elemental Analysis: Calcd. for 2.009 : 0.83 (wt. basis) PEG-8000
and paroxetine HCl: % C, 56.82; % H, 8.07; % N, 1.04; % Cl, 2.83.
Found: % C, 56.71; % H, 8.28; % N, 1.00; % Cl, 3.44.
EXAMPLE 2
PEG-8000/Paroxetine Free-Base, 2:1 wt Basis; Solution Method
To a 200 mL round bottom flask (equipped with a small magnetic stir
bar, rubber septa) was added PEG-8000 (10.0 g) and methanol (140
mL). Paroxetine free-base (4.994 g) was added and stirred about 5
minutes until completely dissolved.
In a separate procedure, methanolic HCl was prepared by bubbling
gaseous HCl (9.81 g) into weighed solution of methanol (50 mL).
This standard solution (0.196 g/mL) could be used for other
experiments.
Methanolic HCl (5 ml), prepared above, was added to the 200 mL
flask and stirring continued for 10 minutes. The stir-bar was
removed, the flask was placed on a rotary evaporator and
concentrated with a bath temperature at 35.degree. C. Once a thick
paste was obtained the flask was placed under static high pressure
vacuum, which was continued 18 hours. On occasion, the material was
scraped free from the sides of the flask to assist in the removal
of residual volatiles. The product was scraped from the flask and
could be ground/milled to an acceptable particle size.
.sup.1 H NMR analysis (CDCl.sub.3) were wholly consistent with a
mixture of PEG and paroxetine hydrochloride, and shows the expected
resonance for PEG (3.63, m) and the characteristic signal for
paroxetine hydrochloride (2.03, br. d). No residual methanol was
detected.
Elemental Analysis: Calcd. for 10.000: 5.54 (wt. basis) PEG-8000
and paroxetine HCl: % C, 57.31; % H, 7.86; % N, 1.27; % Cl, 3.43.
Found: % C, 57.31; % H, 8.07; % N, 1.21; % Cl, 4.38.
EXAMPLE 3
PEG-8000/Paroxetine Free-Base, 4:1 wt Basis, Solution Method
Using PEG-8000 (4.013 g) and paroxetine free-base (1.015 g), and
methanolic HCl (1 mL of a 0.19 g/mL solution) and the method of
Example 2, a solid dispersion of PEG/paroxetine hydrochloride 4:1
wt basis was prepared.
.sup.1 H NMR analysis (CDCl.sub.3) were wholly consistent with a
mixture of PEG and paroxetine hydrochloride, and shows the expected
resonance for PEG-8000 (3.63, m) and the characteristic signal for
paroxetine hydrochloride (2.03, br. d). No residual methanol was
detected.
Elemental Analysis: Calcd. for 4.013:1.126 (wt. basis) PEG-8000 and
paroxetine HCl: % C, 56.23; % H, 8.32; % N, 0.78; % Cl, 2.11.
Found: % C, 56.11; % H, 8.60; % N, 0.72; % Cl, 2.63.
EXAMPLE 4
PEG-8000/Paroxetine Free-Base, 1:1 wt Basis, Solution Method using
ethanolic HCl
An ethanolic HCl solution was prepared by bubbling HCl gas (3.23 g)
into a solution (50 mL) of absolute ethanol.
Using PEG-8000 (2.007 g) and paroxetine free-base (2.066 g), in a
mixture of ethanol (15 mL) and methanol (8 mL), was added ethanolic
HCl (3 mL) and the method of Example 2, a solid dispersion of
PEG/paroxetine hydrochloride 1:1 wt basis was prepared.
.sup.1 H NMR analysis (CDCl.sub.3) were wholly consistent with a
mixture of PEG and paroxetine hydrochloride, and shows the expected
resonance for PEG (3.63, m) and the characteristic signal for
paroxetine hydrochloride (2.03, br. d). 5% residual ethanol (wt
basis) was detected.
Elemental Analysis: Calcd. for 2.007:2.292 (wt. basis) PEG-8000 and
paroxetine HCl: % C, 58.77; % H, 7.29; % N, 1.90; % Cl, 5.15.
Found: % C, 59.18; % H, 7.72; % N, 1.98; % Cl, 4.95.
EXAMPLE 5
PVP 29/32K/Paroxetine Free-Base, 2:1 wt Basis, Solution Method
Using PVP 29/32K (2.077 g), paroxetine free-base (1.008 g),
methanol (28 mL), methanolic HCl (1.0 mL of a 0.196 g/mL solution)
and the method of Example 2, a solid dispersion of PVP/paroxetine
hydrochloride, 2:1 wt basis, was prepared.
.sup.1 H NMR analysis (CDCl.sub.3) were wholly consistent with a
mixture of PVP and paroxetine hydrochloride, and shows the expected
resonances for PVP (series of br. m 3.4-1.6) and the characteristic
signal for paroxetine hydrochloride (2.03, br. d). 4% methanol (wt
basis) was detected.
Elemental Analysis: Calcd. for 2.077:1.118 (wt. basis) PVP and
paroxetine HCl: % C, 61.13; % H, 7.74; % N, 8.82; % Cl, 5.89.
Found: % C, 62.49; % H, 7.63; % N, 9.12; % Cl, 6.33.
EXAMPLE 6
PEG-8000/Paroxetine Free-Base, 2:1 wt Basis; Solution Method
As in Example 2, using ethanol instead of methanol as solvent,
ethanolic HCl (solution prepared in Example 4), PVP 29/32K
/paroxetine free-base, 2.006:1.048 (wt basis).
.sup.1 H NMR analysis (CDCl.sub.3) were wholly consistent with a
mixture of PVP and paroxetine hydrochloride, and shows the expected
resonances for PVP (series of br. m 3.4-1.6) and the characteristic
signal for paroxetine hydrochloride (2.03, br. d). 14% ethanol (wt
basis) was detected.
Elemental Analysis: Calcd. for 2.006:1.048:0.124 (wt. basis)
PVP/paroxetine HCl/ HCl: % C, 59.96; % H, 7.23; % N, 8.59; % Cl,
7.07. Found: % C, 61.39; % H, 7.32; % N, 8.67; % Cl, 7.96.
Using the methods described above and modifications thereof the
following additional examples could be prepared by one skilled in
the art:
______________________________________ HCl Example Excipient
Ratio.sup.1 equivalent Method.sup.2
______________________________________ 7 PVP 1/1 1.0 Solution 8 PVP
2/1 1.0 Solution 9 PVP 3/1 1.0 Solution 10 PEG 1/1 1.0 Solution 11
PEG 2/1 1.0 Solution 12 PEG 3/1 1.0 Solution 13 PEG 4/1 1.0
Solution 14 PEG 1/1 excess Fusion 15 PEG 3/1 excess Fusion 16 PEG
4/1 excess Fusion ______________________________________ .sup.1
Weight basis of Excipient to Paroxetine freebase .sup.2 See Example
2 for Solution Method, Example 1 for Fusion.
Dosage and Formulation
The method of this invention can be administered by any means that
produces contact of the active agent with the agent's site of
action, serotonin re-uptake inhibition, in the body of a mammal.
They can be administered by any conventional means available for
use in conjunction with pharmaceuticals, either as individual
therapeutic agents or in a combination of therapeutic agents.
The dosage of the novel compounds of this invention administered
will, of course, vary depending upon known factors, such as the
pharmacodynamic characteristics of the particular agent and its
mode and route of administration; the age, health and weight of the
recipient; the nature and extent of the symptoms; the kind of
concurrent treatment; the frequency of treatment; and the effect
desired. A daily dosage of active ingredient can be expected to be
about 0.001 to 10 milligrams per kilogram of body weight.
Dosage forms (compositions suitable for administration) contain
from about 0.1 milligram to about 100 milligrams of active
ingredient per unit. In these pharmaceutical compositions the
active ingredient will ordinarily be present in an amount of about
0.5-50% by weight based on the total weight of the composition.
The active ingredient can be administered orally in solid dosage
forms, such as capsules, tablets, and powders.
Gelatin capsules contain the active ingredient and powdered
carriers, such as lactose, starch, cellulose derivatives, magnesium
stearate, stearic acid, and the like. Similar diluents can be used
to make compressed tablets. Both tablets and capsules can be
manufactured as sustained release products to provide for
continuous release of medication over a period of hours. Compressed
tablets can be sugar coated or film coated to mask any unpleasant
taste and protect the tablet from the atmosphere, or enteric coated
for selective disintegration in the gastrointestinal tract.
Suitable pharmaceutical excipients are described in Remington's
Pharmaceutical Sciences, Mack Publishing Company, a standard
reference text in this field.
Useful pharmaceutical dosage-forms for administration of the
compounds of this invention can be illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard
two-piece hard gelatin capsules each with 10 milligrams of powdered
active ingredient, 150 milligrams of lactose, 50 milligrams of
cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean
oil, cottonseed oil or olive oil is prepared and injected by means
of a positive displacement pump into gelatin to form soft gelatin
capsules containing 10 milligrams of the active ingredient. The
capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures
so that the dosage unit was 10 milligrams of active ingredient, 0.2
milligrams of colloidal silicon dioxide, 5 milligrams of magnesium
stearate, 275 milligrams of microcrystalline cellulose, 11
milligrams of starch and 98.8 milligrams of lactose. Appropriate
coatings may be applied to increase palatability or delay
absorption.
The following examples further illustrate a specific embodiment of
the present invention, and is considered an illustrative, but not
limiting, description of the invention.
EXAMPLE 17
A 20 mg paroxetine base (as the HCl salt) tablet using a solid
dispersion as described in Example 8
______________________________________ gm/1000 Ingredient mg/tablet
tablet batch ______________________________________ Paroxetine HCl*
22.21 22.21 Polyvinylpyrrolidone* 40.00 40.00 Dibasic dicalcium
210.79 210.79 phosphate dihydrate Sodium Starch Glycolate 24.00
24.00 Magnesium Stearate 3.00 3.00 Total 300 mg 300 gm
______________________________________ *Theoretical quantities for
a solid dispersion of Paroxetine HCl and polyvinylpyrrolidone as
described in Example #8.
Procedure: Mill the paroxetine HCl/polyvinylpyrrolidone solid
dispersion by passing through a 20 mesh screen. Blend the milled
solid dispersion with the dibasic dicalcium phosphate dihydrate,
sodium starch glycolate and magnesium stearate. Compress tablets to
a weight of 300 mg with a tablet hardness of approximately 17
Strong-Cobb Units.
EXAMPLE 18
A 20 mg Paroxetine Base (as the HCl Salt) Tablet using a Solid
Dispersion as Described in Example 11
______________________________________ gm/1000 Ingredient mg/tablet
tablet batch ______________________________________ Paroxetine HCl*
22.21 22.21 Polyethylene glycol* 40.00 40.00 Dibasic dicalcium
210.79 210.79 phosphate dihydrate Sodium Starch Glycolate 24.00
24.00 Magnesium Stearate 3.00 3.00 Total 300 mg 300 gm
______________________________________ *Theoretical quantities for
a solid dispersion of Paroxetine HCl and polyethylene glycol as
described in Example #11.
Procedure: Mill the paroxetine HCl/polyethylene glycol solid
dispersion by passing through a 20 mesh screen. Blend the milled
solid dispersion with the dibasic dicalcium phosphate dihydrate,
sodium starch glycolate and magnesium stearate. Compress tablets to
a weight of 300 mg with a tablet hardness of approximately 17
Strong-Cobb Units.
* * * * *